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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
31

The Effect of Rosiglitazone on Bone Quality in a Rat Model of Insulin Resistance and Osteoporosis

Sardone, Laura Donata 11 January 2011 (has links)
Rosiglitazone (RSG) is an insulin-sensitizing drug used to treat Type 2 Diabetes Mellitus (T2DM). Clinical trials show that women taking RSG experience more limb fractures than patients taking other T2DM drugs. The purpose of this study is to understand how RSG (3mg/kg/day and 10mg/kg/day) and the bisphosphonate alendronate (0.7mg/kg/week) alter bone quality in the male, female and female ovariectomized (OVX) Zucker fatty rat model over a 12 week period. Bone quality was evaluated by mechanical testing of cortical and trabecular bone. Microarchitecture, bone mineral density (BMD), cortical bone porosity, bone formation/resorption and mineralization were also measured. Female OVX RSG10mg/kg rats had significantly lower vertebral BMD and compromised trabecular architecture versus OVX controls. Increased cortical porosity and decreased mechanical properties occurred in these rats. ALN treatment prevented these negative effects in the OVX RSG model. Evidence of reduced bone formation and excess bone resorption was detected in female RSG-treated rats.
32

Obesity associated colon tumorigenesis: An assessment of tumor phenotype

Saxena, Swati January 2006 (has links)
Colon cancer and obesity are two significant and related pathological states with multiple etiological factors. In this dissertation, it was hypothesized that tumor growth is accelerated in the altered state of obesity due to their resistance towards tumor necrosis factor-alpha (TNF-alpha) mediated cytotoxicity. Physiologically elevated TNF-alpha in an obese state induces increased nuclear transcription factor-kB (NF-kB) activity, known to transcribe genes crucial to cell survival. Insulin resistance, oxidative stress, and a pro-inflammatory environment are few of the biological consequences of TNF-alpha and NF-kB pathway activation, and further contribute to disease progression. <br /><br /> Three major studies were conducted to investigate phenotypical changes in obesity associated tumors. Firstly, characteristics of the TNF-alpha resistant phenotype were preliminarily assessed by evaluating the effects of exogenous TNF-alpha treatment to HT-29 cells. Elevated levels of NF-kB in response to exogenous TNF-alpha gave an indication that this pathway is critical for cell survival. Furthermore, upregulation of TNF-alpha receptor 2 (TNFR2) suggested another strategy by which the cells were utilizing exogenous TNF-alpha for a survival advantage. Inhibition of NF-kB via St. John?s Wort treatment demonstrated that HT-29 cells may be sensitized towards TNF-alpha mediated cytotoxicity. <br /><br /> Zucker obese (Zk-Ob), Zucker lean (Zk-Ln), and Sprague Dawley (SD) animal models were used to assess tumor phenotype <em>in vivo</em>. Remarkable physiological differences between genotypes were observed. Zk-Ob rats had significantly higher body and organ weights as well as plasma TNF- alpha, insulin, leptin, and oxidative markers than Zk-Ln and SD animals. Tumor incidence and multiplicity were also notably higher in Zk-Ob rats. Protein analyses demonstrated increased levels of TNF-alpha, TNFR2, NF-kB, IkB kinase beta (IKKbeta), insulin receptor (IR), insulin like growth factor-I-receptor (IGF-IR), and mitogen activated protein kinase (MAPK) in Zk-Ob tumors than Zk-Ln counterparts. In all groups, tumors generally had higher protein expression than surrounding, normal appearing colonic mucosa. It is well known that these molecules are involved in signaling pathways that influence and co-operate with each other in rendering growth autonomy to tumor tissue. <br /><br /> A higher number of lesions in the distal than proximal colon in Zk-Ob rats was observed, supporting the emerging concept that genotype/physiological state of the host affects development and distribution of tumors. Thus, a third study was conducted to explore differences between distal and proximal tumor phenotype. Results demonstrated that expression of TNFR2, NF-kB, IR, IGF-IR, and MAPK p44 were significantly higher in distal than proximal tumors. This observation suggested that development of tumors in different regions of the colon varied under the same physiological conditions. Moreover, phenotype of distal tumors appeared to be upregulating survival pathways in comparison to proximal lesions, possibly explaining the higher tumor incidence in the distal colon. <br /><br /> Research documented in this thesis supported the hypothesis that the physiological status of the host intricately affects tumor phenotype. In particular, the TNF-alpha resistant phenotype was most prominent in Zk-Ob tumors, and appeared to be associated with upregulation of multiple signaling pathways cooperating towards tumorigenesis.
33

An Assessment of Pyridoxine as a Biological Response Modifier During Colon Carcinogenesis

Kular, Aneta 04 October 2007 (has links)
The main objective of this proposal was to investigate the effect of vitamin B6 on colon carcinogenesis in vivo. Two in vivo studies were conducted to determine the role of vitamin B6 as a biological modifier of colon carcinogenesis. It is hypothesized that vitamin B6 may serve as an antioxidant in vivo and will modulate colon carcinogenesis. In the first study, a 2X3 factorial experimental design was used to determine if three different levels of vitamin B6, classified as low, normal and high in conjunction with two different levels of protein intake, classified as normal or high, will affect post-initiation stages of colon carcinogenesis, in Sprague-Dawley rats. Male Sprague-Dawley male were injected with azoxymethane for two weeks (15mg/kg/week) and then one week later they were allocated to different dietary treatment groups. After eight weeks, the effects of dietary treatment on hematological status, oxidative stress markers and antioxidant enzymes, as well as enumeration of preneoplastic lesions, aberrant crypt foci (ACF), were evaluated. The lowest level of vitamin B6 intake with a high protein diet reduced the growth and development of ACF. Vitamin B6 had no significant effect on the oxidative stress markers. The level of protein was an important variable in modulating the levels of 3-nitrotyrosine and 8-OH-DG which were lower in high protein groups than normal protein counterparts. The objective of the second study was to investigate if a supraphysiological (5 fold higher than normal level) dosage of vitamin B6 could have an antioxidant effect in a metabolically compromised state like obesity and thereby lower the risk of colon cancer. Female Zucker obese (Zk-OB) rats received normal (Zk-OBN, 7 mg/kg) or high (Zk-OBH, 35 mg/kg) vitamin B6 (Pyridoxine-HCl) diets two weeks prior to, during and six weeks following injection with colon carcinogen AOM. The effects of supplemental vitamin B6 on hematological status, oxidative stress markers and antioxidant enzymes, as well as enumeration of ACF were carried out. High intake of vitamin B6 significantly lowered liver weights and plasma cholesterol compared to the normal intake (p≤0.05). Zk-OBH rats had significantly reduced number of ACF compared to Zk-OBN (p≤0.05). Hepatic GSH increased in the ZK-OBH group with a concomitant decrease in GPx activity. The findings demonstrate that in Zucker Obese rats, a high B6 intake augmented the antioxidant potential and decreased sensitivity to colon carcinogenesis. These findings suggest that high vitamin B6 plays an important therapeutic role in the compromised state of obesity.
34

Assessment of the cell cycle proteins Cdc7 and PCNA as markers of colon carcinogenesis in obese and lean rats

Wood, Katherine January 2009 (has links)
Obesity increases the risk of colon cancer as well as the expression of many cancer markers, ostensibly due to the interaction between insulin resistance and adipocyte production of hormones, mitogens and cytokines which collaborate to enhance proliferation signaling and impair the DNA damage response. Cdc7 and PCNA are both proteins involved in the DNA damage response as well as DNA replication. Both have also been shown to be upregulated in human tumours. To assess Cdc7 and PCNA roles during the DNA damage response in obese and lean animals, we administered azoxymethane (AOM), a colon-specific carcinogen, to obese and lean rats. Cdc7 and PCNA levels in colonic mucosal protein extracts from obese Zucker rats were compared with those from their lean counterparts. Significant differences were seen between lean and obese animals 3 hours post-AOM (lean Cdc7 levels > obese Cdc7 levels) and 24 hours post-AOM (lean PCNA levels > obese PCNA levels). This result suggests an impaired checkpoint response in obese animals relative to lean animals and supports a previously reported early role for Cdc7 in the checkpoint signaling cascade relative to a later role of PCNA in DNA damage repair. At the time tumours appeared (32 weeks post-AOM), colonic mucosal Cdc7 levels of obese rats exceeded that of their lean counterparts, suggesting that the obese metabolic environment causes upregulation of Cdc7 in obese rat epithelia. Cdc7 and PCNA levels were then compared between tumours and mucosa in obese and Sprague Dawley rats. Tumour Cdc7 levels were upregulated relative to mucosal levels in more samples than tumour PCNA levels, suggesting Cdc7 may be a more sensitive tumour marker. No significant differences in Cdc7 levels were seen between obese tumours and mucosa, likely due to elevation of obese mucosal Cdc7 levels. However, Sprague Dawley (non-obese) rats showed significantly higher Cdc7 and PCNA levels in tumours than mucosa, consistent with previous studies in human tissues. These results suggest that Cdc7 may be a more sensitive tumour marker than PCNA, but that its utility as a biomarker of colon cancer is dependent on the metabolic state (leanness) of the individual.
35

Obesity associated colon tumorigenesis: An assessment of tumor phenotype

Saxena, Swati January 2006 (has links)
Colon cancer and obesity are two significant and related pathological states with multiple etiological factors. In this dissertation, it was hypothesized that tumor growth is accelerated in the altered state of obesity due to their resistance towards tumor necrosis factor-alpha (TNF-alpha) mediated cytotoxicity. Physiologically elevated TNF-alpha in an obese state induces increased nuclear transcription factor-kB (NF-kB) activity, known to transcribe genes crucial to cell survival. Insulin resistance, oxidative stress, and a pro-inflammatory environment are few of the biological consequences of TNF-alpha and NF-kB pathway activation, and further contribute to disease progression. <br /><br /> Three major studies were conducted to investigate phenotypical changes in obesity associated tumors. Firstly, characteristics of the TNF-alpha resistant phenotype were preliminarily assessed by evaluating the effects of exogenous TNF-alpha treatment to HT-29 cells. Elevated levels of NF-kB in response to exogenous TNF-alpha gave an indication that this pathway is critical for cell survival. Furthermore, upregulation of TNF-alpha receptor 2 (TNFR2) suggested another strategy by which the cells were utilizing exogenous TNF-alpha for a survival advantage. Inhibition of NF-kB via St. John?s Wort treatment demonstrated that HT-29 cells may be sensitized towards TNF-alpha mediated cytotoxicity. <br /><br /> Zucker obese (Zk-Ob), Zucker lean (Zk-Ln), and Sprague Dawley (SD) animal models were used to assess tumor phenotype <em>in vivo</em>. Remarkable physiological differences between genotypes were observed. Zk-Ob rats had significantly higher body and organ weights as well as plasma TNF- alpha, insulin, leptin, and oxidative markers than Zk-Ln and SD animals. Tumor incidence and multiplicity were also notably higher in Zk-Ob rats. Protein analyses demonstrated increased levels of TNF-alpha, TNFR2, NF-kB, IkB kinase beta (IKKbeta), insulin receptor (IR), insulin like growth factor-I-receptor (IGF-IR), and mitogen activated protein kinase (MAPK) in Zk-Ob tumors than Zk-Ln counterparts. In all groups, tumors generally had higher protein expression than surrounding, normal appearing colonic mucosa. It is well known that these molecules are involved in signaling pathways that influence and co-operate with each other in rendering growth autonomy to tumor tissue. <br /><br /> A higher number of lesions in the distal than proximal colon in Zk-Ob rats was observed, supporting the emerging concept that genotype/physiological state of the host affects development and distribution of tumors. Thus, a third study was conducted to explore differences between distal and proximal tumor phenotype. Results demonstrated that expression of TNFR2, NF-kB, IR, IGF-IR, and MAPK p44 were significantly higher in distal than proximal tumors. This observation suggested that development of tumors in different regions of the colon varied under the same physiological conditions. Moreover, phenotype of distal tumors appeared to be upregulating survival pathways in comparison to proximal lesions, possibly explaining the higher tumor incidence in the distal colon. <br /><br /> Research documented in this thesis supported the hypothesis that the physiological status of the host intricately affects tumor phenotype. In particular, the TNF-alpha resistant phenotype was most prominent in Zk-Ob tumors, and appeared to be associated with upregulation of multiple signaling pathways cooperating towards tumorigenesis.
36

An Assessment of Pyridoxine as a Biological Response Modifier During Colon Carcinogenesis

Kular, Aneta 04 October 2007 (has links)
The main objective of this proposal was to investigate the effect of vitamin B6 on colon carcinogenesis in vivo. Two in vivo studies were conducted to determine the role of vitamin B6 as a biological modifier of colon carcinogenesis. It is hypothesized that vitamin B6 may serve as an antioxidant in vivo and will modulate colon carcinogenesis. In the first study, a 2X3 factorial experimental design was used to determine if three different levels of vitamin B6, classified as low, normal and high in conjunction with two different levels of protein intake, classified as normal or high, will affect post-initiation stages of colon carcinogenesis, in Sprague-Dawley rats. Male Sprague-Dawley male were injected with azoxymethane for two weeks (15mg/kg/week) and then one week later they were allocated to different dietary treatment groups. After eight weeks, the effects of dietary treatment on hematological status, oxidative stress markers and antioxidant enzymes, as well as enumeration of preneoplastic lesions, aberrant crypt foci (ACF), were evaluated. The lowest level of vitamin B6 intake with a high protein diet reduced the growth and development of ACF. Vitamin B6 had no significant effect on the oxidative stress markers. The level of protein was an important variable in modulating the levels of 3-nitrotyrosine and 8-OH-DG which were lower in high protein groups than normal protein counterparts. The objective of the second study was to investigate if a supraphysiological (5 fold higher than normal level) dosage of vitamin B6 could have an antioxidant effect in a metabolically compromised state like obesity and thereby lower the risk of colon cancer. Female Zucker obese (Zk-OB) rats received normal (Zk-OBN, 7 mg/kg) or high (Zk-OBH, 35 mg/kg) vitamin B6 (Pyridoxine-HCl) diets two weeks prior to, during and six weeks following injection with colon carcinogen AOM. The effects of supplemental vitamin B6 on hematological status, oxidative stress markers and antioxidant enzymes, as well as enumeration of ACF were carried out. High intake of vitamin B6 significantly lowered liver weights and plasma cholesterol compared to the normal intake (p≤0.05). Zk-OBH rats had significantly reduced number of ACF compared to Zk-OBN (p≤0.05). Hepatic GSH increased in the ZK-OBH group with a concomitant decrease in GPx activity. The findings demonstrate that in Zucker Obese rats, a high B6 intake augmented the antioxidant potential and decreased sensitivity to colon carcinogenesis. These findings suggest that high vitamin B6 plays an important therapeutic role in the compromised state of obesity.
37

Assessment of the cell cycle proteins Cdc7 and PCNA as markers of colon carcinogenesis in obese and lean rats

Wood, Katherine January 2009 (has links)
Obesity increases the risk of colon cancer as well as the expression of many cancer markers, ostensibly due to the interaction between insulin resistance and adipocyte production of hormones, mitogens and cytokines which collaborate to enhance proliferation signaling and impair the DNA damage response. Cdc7 and PCNA are both proteins involved in the DNA damage response as well as DNA replication. Both have also been shown to be upregulated in human tumours. To assess Cdc7 and PCNA roles during the DNA damage response in obese and lean animals, we administered azoxymethane (AOM), a colon-specific carcinogen, to obese and lean rats. Cdc7 and PCNA levels in colonic mucosal protein extracts from obese Zucker rats were compared with those from their lean counterparts. Significant differences were seen between lean and obese animals 3 hours post-AOM (lean Cdc7 levels > obese Cdc7 levels) and 24 hours post-AOM (lean PCNA levels > obese PCNA levels). This result suggests an impaired checkpoint response in obese animals relative to lean animals and supports a previously reported early role for Cdc7 in the checkpoint signaling cascade relative to a later role of PCNA in DNA damage repair. At the time tumours appeared (32 weeks post-AOM), colonic mucosal Cdc7 levels of obese rats exceeded that of their lean counterparts, suggesting that the obese metabolic environment causes upregulation of Cdc7 in obese rat epithelia. Cdc7 and PCNA levels were then compared between tumours and mucosa in obese and Sprague Dawley rats. Tumour Cdc7 levels were upregulated relative to mucosal levels in more samples than tumour PCNA levels, suggesting Cdc7 may be a more sensitive tumour marker. No significant differences in Cdc7 levels were seen between obese tumours and mucosa, likely due to elevation of obese mucosal Cdc7 levels. However, Sprague Dawley (non-obese) rats showed significantly higher Cdc7 and PCNA levels in tumours than mucosa, consistent with previous studies in human tissues. These results suggest that Cdc7 may be a more sensitive tumour marker than PCNA, but that its utility as a biomarker of colon cancer is dependent on the metabolic state (leanness) of the individual.
38

Nobody Else Was Laughing: Dani Levy's Use of Film Humor to Approach German History

Johnson, Courtney C. January 2010 (has links)
Swiss-German director Dani Levy uses humor to explore recent German history in his films "Alles auf Zucker" (2004) and "Mein Führer: Die wirklich wahrste Wahrheit über Adolf Hitler" (2007). In a move unusual for German-speaking film directors, Levy pokes fun at Adolf Hitler and his regime in "Mein Führer." Levy also plays with the tension among formerly estranged members of a Jewish family in "Alles auf Zucker" to create a metaphor for the strained relations in reunified Germany.This project explores how Levy uses humor to break taboos in contemporary German society and prompt audiences through humor to critical debate about recent German history and its implications for contemporary and future society. This analysis is important to the German-speaking world and global audiences because Levy's work begs viewers to ponder what they can laugh at, who is allowed to make jokes, and how comedy can promote debate about societal norms and taboos.
39

Effects of endocannabinoid (CB1) receptor antagonism on insulin resistance in a rodent model of metabolic syndrome

Lindborg, Katherine Ann January 2010 (has links)
The endocannabinoid system is a novel pharmacological target in the treatment of metabolic syndrome. Antagonism of the endocannabinoid-1 receptor (CB1R) leads to a transient reduction in food intake, a sustained decrease in body weight and an improvement in metabolic parameters in animal models of obesity. Skeletal muscle is the primary tissue involved in glucose uptake in response to insulin, and insulin sensitivity of skeletal muscle is vital to the maintenance of whole-body euglycemia. Little is known regarding the effects of CB1R antagonism on skeletal muscle glucose transport activity. The purpose of this dissertation was to test the hypothesis that antagonism of the CB1R activates signaling molecules of the insulin signaling pathway to increase glucose transport activity in normal and insulin-resistant skeletal muscle, thereby improving whole-body glucose tolerance. CB1R antagonism with SR141716 directly enhanced basal and insulin-stimulated glucose transport activity in skeletal muscle from lean and obese Zucker while activation of the CB1R with ACEA, decreased glucose transport activity. Key proteins associated with regulation of glucose transport activity were not altered by either CB1R agonism (ACEA) or antagonism (SR141716). Chronic CB1R antagonist treatment (10 mg/kg SR141716 i.p. / 14 days) also enhanced insulin-stimulated glucose transport activity in skeletal muscle of both lean and obese animals, again with no alteration in relevant signaling factors. Plasma free fatty acids (FFAs) were decreased in chronically-treated lean and obese animals and whole-body insulin sensitivity was improved in obese Zucker rats. The enhanced insulin sensitivity seen in chronically-treated obese animals was associated with a dramatic reduction in insulin secretion following a glucose challenge. Acute CB1R antagonism in obese animals also elicited a reduction in insulin secretion following a glucose challenge; however, with no improvement of whole-body insulin sensitivity. Acute CB1R antagonist treatment did not alter skeletal muscle glucose transport activity or circulating FFAs for any animals. These data suggest that although CB1R antagonism directly enhances basal and insulin stimulated glucose transport in skeletal muscle of lean and obese rats, direct action on the skeletal muscle is not responsible for the improvement in insulin-stimulated glucose transport activity and whole-body insulin sensitivity seen in chronically-treated obese animals.
40

The Effects of High Protein Diets on Metabolic Syndrome Parameters in the fa/fa Zucker Rat

Wojcik, Jennifer 17 September 2014 (has links)
Despite inconsistent results in the literature, high protein diets are being promoted for the management of metabolic syndrome parameters primarily due to their proposed favorable effects on weight loss. Therefore, lean and fa/fa Zucker rats were given normal and high protein diets with varying protein sources for 12 weeks. A high protein diet with a mixture of animal and plant protein sources was the most effective for improving metabolic syndrome parameters, specifically insulin resistance and hepatic steatosis. A high protein soy diet was the second most effective diet, while a high protein casein diet demonstrated no benefits compared to the other two high protein diets and minimal benefits compared to a normal protein casein diet. Interestingly, high protein diets did not affect body weight regardless of protein source. These findings suggest that the source of protein within a high protein diet is critical for improving metabolic syndrome parameters and that improvements can be observed independent of weight loss.

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